Costea Julia, Schoeberl Ursula E, Malzl Daniel, von der Linde Maximilian, Fitz Johanna, Gupta Ankit, Makharova Marina, Goloborodko Anton, Pavri Rushad
Research Institute of Molecular Pathology (IMP), Vienna Biocenter, Campus-Vienna-Biocenter-1, 1030 Vienna, Austria.
IMBA - Institute of Molecular Biotechnology, Vienna Biocenter, Dr.-Bohr-Gasse 3, 1030 Vienna, Austria.
Mol Cell. 2023 Mar 2;83(5):681-697.e7. doi: 10.1016/j.molcel.2023.01.014. Epub 2023 Feb 2.
Interactions between transcription and cohesin-mediated loop extrusion can influence 3D chromatin architecture. However, their relevance in biology is unclear. Here, we report a direct role for such interactions in the mechanism of antibody class switch recombination (CSR) at the murine immunoglobulin heavy chain locus (Igh). Using Tri-C to measure higher-order multiway interactions on single alleles, we find that the juxtaposition (synapsis) of transcriptionally active donor and acceptor Igh switch (S) sequences, an essential step in CSR, occurs via the interaction of loop extrusion complexes with a de novo topologically associating domain (TAD) boundary formed via transcriptional activity across S regions. Surprisingly, synapsis occurs predominantly in proximity to the 3' CTCF-binding element (3'CBE) rather than the Igh super-enhancer, suggesting a two-step mechanism whereby transcription of S regions is not topologically coupled to synapsis, as has been previously proposed. Altogether, these insights advance our understanding of how 3D chromatin architecture regulates CSR.
转录与黏连蛋白介导的环挤压之间的相互作用会影响三维染色质结构。然而，它们在生物学中的相关性尚不清楚。在此，我们报道了此类相互作用在小鼠免疫球蛋白重链基因座（Igh）处抗体类别转换重组（CSR）机制中的直接作用。使用Tri-C来测量单等位基因上的高阶多路相互作用，我们发现转录活跃的供体和受体Igh转换（S）序列的并列（联会）是CSR中的关键步骤，它通过环挤压复合物与跨S区域转录活性形成的新生拓扑相关结构域（TAD）边界的相互作用而发生。令人惊讶的是，联会主要发生在靠近3' CTCF结合元件（3'CBE）的位置，而非Igh超级增强子附近，这表明存在一种两步机制，即S区域的转录与联会并非如先前所提出的那样在拓扑结构上相互耦合。总之，这些见解推进了我们对三维染色质结构如何调节CSR的理解。
